Of the approximately 40,000 people diagnosed with primary brain tumors in the United States each year, an estimated 15,000 have glioblastoma multiforme (GBM), a WHO grade IV malignant glioma (Mrugala, et al Nat Clin Pract Oncol 5, 476-486 (2008)). Despite considerable research efforts, the prognosis for GBM remains poor: median survival with standard-of-care therapy (surgery, systemic chemotherapy with temozolomide, and radiation) is 14.6 months (Stupp et al., N Engl J Med 352, 987-996 (2005)) and five-year survival is 9.8% (Stupp et al., The lancet oncology 10, 459-466 (2009)), with the vast majority of GBMs recurring within 2 cm of the original tumor focus (Hochberg, et al. Neurology 30, 907-911 (1980)). Histopathologically, GBM is characterized by its infiltrative nature and cellular heterogeneity, leading to a number of challenges that must be overcome by any presumptive therapy.
The blood-brain barrier (BBB) is a major obstacle to treating GBM (J. Kreuter, Adv Drug Deliv Rev 47, 65-81 (2001)). Clinical trials have demonstrated that the BBB can be safely bypassed with direct, locoregional delivery of therapeutic agents. For example, local implantation of a drug-loaded biodegradable polymer wafer (presently marketed as Gliadel®), which slowly releases carmustine (BCNU) over a prolonged period, is a safe and effective method for treating GBM. However, use of the Gliadel® wafer results in only modest improvements in patient survival, typically two months. (H. Brem et al., J Neurosurg 74, 441-446 (1991); H. Brem et al., Lancet 345, 1008-1012 (1995)). These wafers produce high interstitial drug concentrations in the tissue near the implant, but because drugs move from the implant into the tissue by diffusion—penetration into tissue is limited to approximately 1 mm, which could limit their efficacy (Fung, et al. Pharm Res 13, 671-682 (1996); Fung et al., Cancer Res 58, 672-684 (1998)).
Drug developers have long been frustrated by the BBB, which severely limits the types of agents that can be tested for activity in the brain. Current therapy for glioblastoma multiforma (GBM) is insufficient, with nearly universal recurrence. Available drug therapies are unsuccessful because they fail to penetrate through the region of the brain containing tumor cells and they fail to kill the cells most responsible for tumor development and therapy resistance, brain cancer stem cells (BCSCs).
Convection-enhanced delivery (CED), in which agents are infused into the brain under a positive pressure gradient, creating bulk fluid movement in the brain interstitium (Bobo et al., Proc Natl Acad Sci USA 91, 2076-2080 (1994)) is safe and feasible (S. Kunwar et al., Neuro Oncol 12, 871-881 (2010); J. H. Sampson et al., Neuro Oncol 10, 320-329 (2008); A. Jacobs et al., Lancet 358, 727-729 (2001)), but CED alone is not sufficient to improve GBM treatment. For example, CED of a targeted toxin in aqueous suspension failed to show survival advantages over Gliadel® wafers (Kunwar et al., Neuro Oncol 12, 871-881 (2010); Sampson et al., J. neurosurg. 113, 301-309 (2010)). While CED of drugs in solution results in increased penetration, most drugs have short half-lives in the brain and, as a result, they disappear soon after the infusion stops Sampson et al (2010); Allard, et al. Biomaterials 30, 2302-2318 (2009). Loading of agents into nanocarriers, such as liposomes, micelles, dendrimers, or nanoparticles, can protect them from clearance. Compared to other carriers, nanoparticles made from the FDA-approved poly(lactide-co-glycolide) (PLGA) are stable, safe, and tunable to control drug release. But CED of PLGA nanoparticles, which are typically 100-200 nm in diameter, has been limited by the failure of particles to move by convection through the brain interstitial spaces (Sawyer, et al. Yale J Biol Med 79, 141-152 (2006); Sawyer et al., Drug Deliv Transl Res 1, 34-42 (2011); Neeves, et al. Brain Res 1180, 121-132 (2007); Chen et al., J Neurosurg 103, 311-319 (2005), which appear to be 38-64 nm in normal brain (Thorne, et al. Proc Natl Acad Sci USA 103, 5567-5572 (2006)) and 7-100 nm in regions with tumor (Hobbs et al., Proc Natl Acad Sci U SA 95, 4607-4612 (1998)).
It is therefore an object of the present invention to provide drug carriers which can penetrate into both normal and cancerous brain interstitial spaces and provide prolonged release of therapeutic agents.